Yr 01-04 products from our NIDA P60 Research Center include: validating our assessments of adolescent conduct and substance problems; identifying a heritable multi-substance phenotype that discriminates patients from controls, correlates with severity of conduct problems, and has a suggestive QTL on Chromosome 9; contributing to the debate on relevant candidate genes; attracting superb post-doctoral fellows; and extensive teaching. Our thesis is: "Identifiable genes of some persons produce a lifelong behavioral disposition toward antisocial behavior. Part of that disposition involves excessive pursuit of exciting appetitive stimuli and unusual disregard of aversive consequences for behavior, a "behavioral disinhibition." These characteristics frequently lead to substance abuse or dependence and to antisocial behaviors. Although partially of genetic origin, the disposition is not immutable. Altering central biochemistry or revising environmental contingencies for behavior may reduce the substance involvement and antisocial behavior of these persons. However, for many persons the genetically-determined disposition will remain, and such treatments must continue indefinitely to have sustained effects. Many conduct-disordered adolescents will develop lifelong antisocial personality disorder; others will not. Genetic influences on the antisocial and substance-dependence problems are greater in these life-course persistent persons, compared to others. Eventually, specification of the genes influencing this behavioral disposition will lead to therapies aimed at the protein products of those genes." Aims are investigating hypotheses arising from this thesis and educating about the thesis. Component I will replicate in 900 families the suggestive QTL found during Yrs 01-04. For sophisticated genetic analyses the Center will conduct long-term follow-ups of former adolescent patient subjects and general-population adolescent controls (Component 2), as well as Colorado's well-known samples of adolescent adoptees (Component 3) and twins (Component 4). Component 5 will implement methods for identifying specific genes influencing substance and conduct problems. Component 6 will support pilot feasibility studies providing preliminary data for future behavioral and genetic research in antisocial drug dependence. An Administrative-Educational Core provides administrative support and oversight and supports a large educational program. An Informatics Core manages and analyses the Center's massive data sets. A Molecular Core provides DNA banking and genotyping for all components.